The alkaloids obtainable from Vinca rosea represent one of the most productive areas of chemistry for drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtainable from the leaves of the plant by extraction and purifiable by chromatography were found to be active. These active anti-neoplastic vinca alkaloids obtained directly from the plant have been found to be dimeric indole-dihydroindole alkaloids representable by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB (vincaleucoblastine, vinblastine) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), leuroformine (Belgian Pat. No. 811,110); leurosidine (vinrosidine) and leurocristine (to be referred to hereafter as vincristine) (both in U.S. Pat. No. 3,205,220).
Two of the above alkaloids, VLB and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases, in humans. The two marketed alkaloids are customarily administered by the i.v. route. Two others, leurosidine and leuroformine, have been on clinical trial in the U.S. or in Europe.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemical reactions which modify one specific functional group of the molecule without affecting other groups have been difficult to develop. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties have been recovered or produced from Vinca rosea extracts, and a determination of their structures has led to the conclusion that these inactive compounds are closely related structurally to, and even isomeric with, the active alkaloids.
One of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives. Many of these are active anti-tumor agents (see U.S. Pat. No. 4,166,810, and Conrad et al. J. Med. Chem., 22, 391 (1979). These compounds are extremely interesting because, for example, the 3-carboxamides of VLB are more active against Ridgeway osteogenic sarcoma and Gardner lymphosarcoma than is VLB, the basic alkaloid from which they are derived. Certain of these amide derivatives approach the activity of vincristine against these two tumors. In particular, 4-desacetyl VLB C-3 carboxamide (vindesine) currently on clinical trial in humans, appears to have less neurotoxicity than does vincristine and to be effective against some of leukemias including those which are vincristine-resistant.
Other amides of VLB and 4-desacetyl VLB which have been described in the literature include the N-ethylamide, the N-(2-hydroxy)ethylamide, the N-(2-methoxy)ethyl amide, the corresponding thio compounds, and the N-n-propylamide.
While VLB and a few other antineoplastic dimeric vinca alkaloids are active when administered by the oral route, far higher doses are required than when utilizing the more conventional intravenous route. Of all the VLB derivatives tested to date, only the oxazolidinedione derivatives of U.S. Pat. Nos. 4,096,148 and 4,160,767 have oral activity at a dosage range approaching that of the i.v. dose. The oral dose levels of these oxazolidinedione derivatives of VLB etc. are higher than the i.v. dose levels for vincristine.
It is an object of this invention to provide a vinca dimer having oral activity and an anti-tumor spectrum approaching the i.v. activity and spectrum of vincristine.